Coxiella burnetii is an intracellular pathogen that causes the human disease Q-fever. Mechanisms by which this bacterial pathogen exploits human cells remain unknown. This project is focused on the activities of virulence determinants in Coxiella that are essential for biogenesis of a vacuole that supports bacterial replication. One of the essential determinants for biogenesis of the Coxiella-containing vacuole (CCV) is the Dot/Icm system, which is a functional type IVb protein secretion machine that promotes infection by delivering bacterial effectors into host cells. We have identified Coxiella mutants that are deficient in effector proteins, which led to the identification of effector proteins that function n vacuole biogenesis. To understand how these effector proteins promote biogenesis of a vacuole that support Coxiella replication we will complete the following aims. Aim 1: Determine how Cig57 and Cig2 modulate host cell functions. Aim 2: Determine why host autophagy is essential for normal CCV biogenesis and fusion. Aim 3: Identify effector proteins that have important roles in relevant cell types.